Oral History Transcript — Dr. John Roberts
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John Roberts; July 27, 2007
ABSTRACT: This is an informal discussion about Professor Roberts’ work in Nuclear Magnetic Resonance. It includes how he got acquainted with Quantum Mechanics. A story about Francis Bitter’s work with a Carbon-13 sample borrowed from Roberts. Collaboration with Varian on building new spectrometers. UV and IR spectroscopy in comparison with NMR. Influence of Felix Bloch’s explanation of the Bloch equations on Roberts. Influence of a series of lectures that Edward Purcell gave on Roberts. Description of NMR magnet stabilization. The origin of MRI. Roberts’ work with protein NMR.
Pavlish:It is July 27, 2007. I am here in Professor John D. Roberts’ office at the California Institute of Technology. Caltech is a legendary place for science.
Pavlish:I am here to ask his advice, himself being a writer as well as a scientist, having written an autobiography and several influential textbooks on NMR in Chemistry, in Organic Chemistry, advice for the historian of science. NMR is huge.
I see a poster outside your office from a talk you gave in 2006.
Can it even be written as a total history? Maybe from 1937, in I. I. Rabi’s laboratory, the detection of magnetic resonance in molecular beams; then, skip to 1945-1946 with the Purcell and Bloch experiments, and then going forward in time.
It is very daunting.
I myself got interested in NMR because I was so excited by the science. But, then at the same time, reading in The New York Times about brain imaging with magnetic resonance.
There was this huge disconnect between being puzzled by the Quantum Mechanics and how can the nuclei precess in this way, and the energy levels and all that. In this conversation we are going to be talking across disciplines because embarrassingly I have never taken Organic Chemistry and I wish I had. I only had Physics and now I am in History.
There are so many disciplines in between: there is physics, there is chemistry, there are many sub-branches of chemistry, there is biology, there is psychology, there are even philosophers getting interested in MRI for moral reasoning.
I am really just here to listen to your advice.
Roberts:I am not really sure what you want. Do you want to know what are the important topics to cover, or at what level to cover? Really, what is it you are looking for?
Pavlish:I am intrigued by this cross-disciplinary function of NMR.
It is mentioned in this ISIS article about you that you were bridging from the physical chemists or the physicists to the organic chemists. It seems like it would then go on to biology. That is a more philosophical question.
Practically, I am looking for concrete things like sources you would recommend.
And then, I do not want to repeat things that you have already written, but maybe some biographical background about how you became acquainted with NMR. But only what you do not have on record already, because if it is on record, then I can go back to it and read it, or look at the documents.
Roberts:When I became acquainted with it is covered pretty well in my autobiography in detail. I think it is important to know where I started from.
When I was an undergraduate at UCLA I had taken Chemistry. There was no mention in any course I took, including Physics, of Quantum Mechanics.
I remember a chemistry book, which is written partially by A. A. Noyes whose name is on the lab across the street and who was a big power here. I remember there was a little piece somewhere about rotational spectra, but it was not part of the class at all. The class, Physical Chemistry, was all about thermodynamics, first.
So I started from ground zero.
I was not very good in Physics, either, partly because, at that time there was not a very good picture of what was going on.
And so, I got thrown into this Quantum Mechanical thing, as I explain in my autobiography, by getting over-confident about what I could explain.
At the time everybody was using resonance to explain the properties of organic compounds.
Now, I do not know what you know about resonance in organic chemistry; it is a very wonderful historical topic by itself.
Pavlish:I remember getting confused by that because I was reading about resonance but it was before NMR so I realized it is a different kind of resonance completely, right?
Roberts:Right, right. It has to do with structural theory rather than with measurements. Why it is called resonance — it was always called that by Pauling. He and other people thought there was a good analogy to the resonance that occurs with coupled pendulums. So, that is why it came along that way.
So, then I got into Quantum Mechanics in a very primitive way, because I had to teach this course. I promised the students that I was going to talk about organic molecules without resonance. So, I had to find out how to do it, because I found out very very quickly that I really did not know enough to give that course in that way. So I had a pretty tough time learning it, particularly when I did not have any Quantum Mechanics before. And so I got into that.
Then, when I got into NMR, it was a big help to have even that simple background to understand more about NMR. So, I wrote a book. I guess it is the white book on the first shelf next to the two things with the red labels, that one, the white one, yes, the small book.
Pavlish:“An Introduction to the Analysis of Spin Spin Splitting in High Resolution Nuclear Magnetic Resonance Spectra.”
Roberts:That had to be in Quantum Mechanics because that is what NMR is really all about. It is a wonderful demonstration of Quantum Mechanics when you see displays generated. You can only understand a lot of that with Quantum Mechanics.
Pavlish:Did you think about the other kind of resonance when you were learning about NMR? Because that is one way, I assume, one could approach the story, is to go back in time and look at different kinds of resonances.
Roberts:My chemical life is one in which I run across something and I see something in depth in there that I can use and I go down that line for a while. As I explain in my autobiography, and I can show you pictures.
I suppose you have heard of Francis Bitter, who was at The National Magnet Lab at MIT. He came in to my place and wanted a sample that I had, with C-13 in it. I did not know what he wanted it for.
He said, “I am going to wrap a wire around it.” I was afraid he was going to open it. It was a very expensive sample. So he ran it, and came back with it. It was intact. He said he had pushed out the magnetic moment of C-13 to several decimal places. He was very happy about that.
And so, I forgot about that, except I always remembered what had happened, but I did not remember why.
Then, I had a visit from a professor at Stanford who was closely acquainted with Bloch and his group at Stanford, and he was telling me about NMR. I did not understand hardly anything he was saying, except that it was going to be a big deal for chemistry.
Pavlish:Who was this?
Roberts:That man was named Richard Ogg. He is a very very bright guy. He was a visiting professor at Harvard at the time.
I still did not understand what he was talking about, but I certainly remembered his enthusiasm.
When that happened I was also a consultant for Dupont. When I got to Dupont on one trip, they said that I could talk to a man there who was working on NMR. He had been a student at MIT and I had been on his PhD exam. So, we had NMR there. That was one of the first in industry. And, he showed me what he could do. His name was Bill Philips, William Philips [spelling?]. He was a real leader of the early use of NMR in chemistry.
When I saw what he could do, then I was convinced. I did not know how it worked, I did not understand the Quantum Mechanics of it or anything else, but I was going to do that because this was an operation that I thought chemistry could do.
We had gone into ultraviolet spectroscopy with the spectrum work on that as a commercial product and infrared spectroscopy in the same way. We were using those tools, hands on, and that was very important to me because I figured that we could do NMR hands on too.
The initial spectrometer was not a big machine but it sure did a lot of wonderful things. So, it got better and better.
As I point out in the ISIS article, we got money to build machines through our order to do particular jobs. I did not want to build the machines, though I threatened to when Varian said that an idea I had would not work.
Then I said, “Alright, then I will buy the equipment and build it myself.”
Ad then they thought about it for a while and they said, “Well, it would work.”
It turned out to be a fabulous product. Basically, it really set NMR up with Carbon as a routine thing.
I had a young man here. He was very ambitious and very hard-working. He did his thesis in two years and nine months and he had sixteen papers.
Pavlish:Oh my gosh. With NMR?
Roberts:I think they were all on Carbon NMR. But they were really a variety of papers. They were not just routine things. Some of them were pretty routine because we had to find out what we could do with it, but some of them were very sophisticated.
Pavlish:I am still a little fuzzy on the differences between radio-frequency spectroscopy, and what you were talking about the different kinds of spectroscopy: IR, UV. What is the unit here? If one was to write a comprehensive history of magnetic resonance, I have been thinking about the unit as the nucleus precessing in the radio-frequency field. I do not know how to delimit the topic.
Roberts:Think about it in terms of electrons. UV spectroscopy has to do with the excitation of electrons to higher orbitals. And so those absorptions are there, they can be understood they can be more or less predicted. But it does not give very precise information about the structure. That is the whole point. It tells you about how the electrons are, what orbitals they go into, and generates something that you can measure quite easily. The Beckman machine was a real advance.
When I went to MIT as an instructor there, what I needed to do my work, I wanted a Beckman spectrometer to do my work, for my own use. I always liked to have control of the machines, when possible. So, we got that.
In the infrared, you start looking at the different frequency range. The ultraviolet is a pretty high frequency and the infrared is a lower frequency. And, what you are doing now is looking at the vibrations of the atoms and bonds and the rotations around bonds and so on. Those fall in particular regions of the spectra. So you have some of them that are at the higher frequency end which involve hydrogen vibrations and so on like in hydrogen bonds.
I do not know if you know what a hydrogen bond is. It is one where you have an O-H group and a hydrogen on that O-H group can get associated with another atom that has an affinity for hydrogen. It is very very important for biology. Very important in carbohydrates, sugars, and compounds like that. They are full of O-H groups. Also, very important in cellulose.
So, those are a little more specific. You can find out more structural information but it still is not really definite because there is no really good way to predict the vibrations and rotations in other than pretty small molecules. And, the other thing that is very important, is that you cannot tell how much there is of each one of the bonds. You can detect their presence, their rotations, but it is hard to use that as an analytical method because the so-called oscillator effect of these vibrations and so on, that you pick up have to be calibrated.
Once you calibrate it with a known compound, you can measure the amount of that compound present, but you have to calibrate it to do well.
Now, NMR is wholly different in that it involves the magnetism of the nuclei. So, now what you get is a very important thing; it is that the strength of the signal, properly obtained, is directly proportional to the amount of stuff that is there. So, you can integrate various signals when you have a mixture, and you can analyze a mixture that way. That is a very very powerful thing.
Then, it turns out, that each atom of different kind, and at a different place on the molecules, and so on, usually has a different frequency in which the nuclei will absorb energy. So you have what is called the chemical shift. Bitter was really measuring the chemical shift, not really the nuclear moment itself. Because the compound had ions in it and other things that caused diamagnetic and paramagnetic effects in the magnetism.
Pavlish:Was Norman Ramsey one of the pioneers of that chemical shift in physics? Did you interact with him at all at Harvard?
Roberts:He was very close in there, yes. I think it was actually discovered by somebody else who was working on nitrogen compounds. But, Ramsey was one of the physicists who understood all that.
I met him; I did not know him very well. I knew Bloch pretty well. Purcell slightly. But, Bloch was so involved with Varian that we became pretty good friends in later life.
Pavlish:Are there any particularly vivid stories of you two together, with Bloch?
Roberts:I do not think it was that kind of a relationship. We were not that close together, but we could talk together about NMR and so on.
I do not remember anything right now. That is the trouble. That is the trouble, you know, sometimes you start thinking about that and after you leave you think, oh, I should have told her about this. I cannot think of anything right now.
Pavlish:You do not have any correspondence with him, do you?
Roberts:Well, I have a lot of correspondence. I do not know whether I’ve got any with Bloch or not.
I often talked to Bloch about his initial paper, which I thought was very, very good for me, when he derived the so-called Bloch equations that explained how the spectrometer worked. That was a real eye-opener for me, to be able to more or less work through that paper.
Pavlish:You mean the 1946 paper? Or his Bloch equation is later?
Roberts:It is not the communication, but the explanation of NMR. He talks about various factors that are involved. I thought it was a good paper.
Pavlish:How did you come to discuss it with him?
Roberts:He was a member of the National Academy and I would see him there.
Purcell did one thing for me that was really great. During this period, [the practitioners of the field?] were not interested in anything but nuclear energies and all this kind of stuff, and isotopes. But they did, for some reason, have Purcell come out and he gave two or three lectures.
At this time, just after we had got an NMR machine, I was figuring out how it worked. And he gave a marvelous series of lectures. He clarified some really important ideas for me. So, I really remember those lectures. They were beautiful lectures. And for somebody who did not know very much, I got a tremendous amount out of those lectures.
I was struggling with the problem at the time and that increased my interest in everything he had to say. But I did not talk to him at the time. I was a little unwashed to do that. I was just messing around. I was taking spectra and getting things that were publishable, but I did not really understand much of what I was doing. I knew that I was getting what Philips had taught me that NMR was going to be really important for chemistry.
But you would be amazed how bad the machine was at the time. We used to take spectra every seven seconds, and then we used hotwire writing on special paper. The paper would go “swish, swish.” [laughs]
We would try to find two spectra that were alike. If we found three, that was really good.
Nowadays, you can run a spectrum for three or four days and it is very stable.
Pavlish:What was the transition like from those hot wire detectors to the oscilloscope? Is this [shows picture from ISIS article] produced with what you were just describing?
This is in the second stage, I would say. What happened originally was that there was so much change in the magnet, the power supply (I can show you a picture). The big power supply is over here. The magnet is over here. This was a key. It was called a super stabilizer. That came and was added on just at the right time for me.
What it did, it was a very simple device. They had a coil wrapped around the magnet. And then they had that coil connected to a galvanometer. So that every time the magnetic field changed, it would make the galvanometer go. So, the galvanometer was set between two phototubes and it had a bright light. And so, it would go either this way or that way. One way would mean you had to turn the field down, the other way would mean you had to turn the field up. It was pretty rapidly responsive. So what happened then is that it tended to level out these oscillations because if it started to change, the galvanometer would go “click”, put some power in and get it back up or go the other way.
And they had special coils; it was not really connected to the power supply itself, but it was connected to special coils that could react quickly. The change in magnetization of coils that big is a slow process. But they had special smaller coils around it that could add just a little bit of magnetic field.
You have to remember that it is an extraordinarily delicate phenomenon in the sense that the kind of information we wanted then was in parts per million. And now it is in parts per billion.
But that means that the magnet has to be stable, and it means that your oscillator that is putting the power into the sample has to be stable. Doing both of those with the equipment that was available at the time was unthought of, really.
Pavlish:This galvanometer stabilized the oscillator or did it stabilize the permanent magnet?
Roberts:They stabilized the magnet. It is not a permanent magnet. It is an electromagnet. It coiled around the pole-faces and reacted to do that.
Pavlish:How did you think of what to put in the spectrometers? Was it straightforward what materials you would take spectra from?
Roberts:I had a lot of problems with the compounds we were working with. [laughs] I would integrate it into my research program when we got an idea.
It was really interesting. At that time everybody who was in the thing realized that there was an enormous world of stuff to do. And so they would send in these letters. There was this feeling of helping everybody do something rather than being in competition. There was so much to do, they wanted people to be helped. There was sort of a fraternity. Then after a while, of course [laughs]. It started to be more competitive.
Pavlish:What journals was that done in? And what years did people do that, just send in ideas?
Roberts:I do not know when it actually started, but you can tell how it developed in the end when they had this battle about who invented MRI. That was a nasty business.
[laughs] I was in a meeting in London one time. They had this man, Damadian, there. Incidentally, at the time that he first got his pictures, he sent me copies of them.
Roberts:Oh, yes. They were Polaroid pictures and they were in color. A couple of my boys then were in medical school [laughs] and I wanted to know what they thought of it. They did not think anything at all of it.
They said, “Geeze, if you cannot do better than that…”
I said, “Well, it is only the beginning.”
Anyhow, Damadian had staked out a claim for MRI and clearly Lauterbur was ahead of him. Although, Damadian had done some interesting work on his own, regarding relaxation times in tumorous tissue.
But anyhow, he was designated as a discussion leader. He got up and started raving and ranting. They had to almost physically remove him.
Roberts:Yes, he was so bitter and so negative. Everybody was embarrassed.
He never got over it. And, he convinced some other people that he really deserved it [the recognition, the Nobel Prize].
Well, he was the first one to use NMR, as far as I know, for human imaging. Those are the images he sent me. But that was not really the invention of MRI.
The embarrassing thing for me, and for a few hundred or a thousand other people who had NMR machines, was that any one of us could have gotten the imaging idea if we had just been thinking ahead. That went on for 15 years before Lauterbur really recognized that what we all knew about was capable of doing something that was really wonderful. I always feel a little dumb when I think about that.
Well, one of the most interesting questions, I think, for the historian, is the new theory in History of Science, of scientific objects. What do scientists look at as a scientific object?
There is a professor who just wrote a book about the pest, the little bug, in Germany. She writes that a pest stepped on underfoot or even marveled at, or just around in the fields is not a scientific object. However, when the scientists start to consider it in that way and analyze it and represent it in different ways, then it becomes a scientific object.
Roberts:What do you mean by a scientific object?
Pavlish:What do I mean? Hmmm.
Pavlish:Let’s see. For NMR, the objects of NMR are the carbon-13, or the hydrogen that you are looking at, or the nucleus. I would say they are scientific objects. You put it in the machine and you analyze it, and you are coming to know the thing there.
Some people call it “the epistemic thing,” but that is just a fancy phrase to mean scientific object.
But then, there are interesting boundary lines between the radiofrequency field that you use to irradiate the scientific object, and then the sample gives it back and you pick up the signal. When it is part of the instrument, I would say it is not a scientific object. It is then a technological tool.
I think that NMR is so rich in questions and beauty and everything and I am wishing for guidance as to how one can tell it as a story so that it has integrity, comprehensiveness, and meaning.
Roberts:Well, you start out doing simple things and you run into things. For example, the structure led to the chemical shift, and then we got into the question about well, what does the splitting tell you?
The splitting gives you wonderful information about the molecule, and that way it is put together.
People developed new tricks to keep improving that.
For us, the first thing was the chemical shift. And then we got the splittings.
I did not really understand the splittings. I was using the same thing that you would have learned in Organic Chemistry that you count on your fingers to find out how much splitting there will be.
But then, one man who was later one of my colleagues, he was at Shell at the time, he published a paper that I just could not understand [laughs].
Later on, when he was a colleague, I got a hold of him on July 4th one time when he was not in motion, and I made him sit for two or three hours and tell me what that was all about. Again, it was one of those things in which you suddenly see the light and I could connect it immediately to the molecular orbital stuff that I had done before.
And so, I set to work to write this book on the theory of spin-spin splitting.
And one of my physical chemistry friends said, “Well, gee, that is a good book for an introduction to Quantum Mechanics. People really ought to do Quantum Mechanics that way. Why don’t you rewrite it for that?”
Well, I think someone could almost use it for that now. It is a wonderful illustration and it is not messed up with the Schrodinger equation and all that stuff. That is what I think makes it really a good introduction. It just does not have the buzz of all those electrons interacting with each other.
Pavlish:And who was this person you talked to for two to three hours at that Fourth of July?
Roberts:Hart McConnel [spelling?]. He is a professor now at Stanford, but he was one of my colleagues. He really understood this whole business really well.
Pavlish:Did you watch the fireworks afterwards on the Fourth of July?
[laughs] I do not remember. I do not think so. I probably had fireworks in my head at that time. [laughs, Pavlish laughs also]
Then the other thing that came along, Philips had demonstrated it to me, but I did not really understand it again, was the way in which you can get chemical reaction rates out of NMR, where the stuff is going back and forth between two forms.
If the motion was slow enough, you could actually cool the sample down and you could slow the equilibrium so much that you could see both things that were in equilibrium. They needed not to have the same structure at all. You could measure the rates of extraordinarily fast reactions in ordinary terms. You could measure reactions that would go, say, in a hundred thousandth of a second or so.
That was an entirely new idea for chemists. That played out to be a very marvelous thing in many connections.
So, we had all those things going on: basically, the chemical shifts, the spin-spin splittings, and the rate effects. And then there are another class of things that are not normally taught in Organic Chemistry. These other things are taught in modern Organic Chemistry courses.
But, the other thing that is involved is nuclear relaxation. That is a very important topic both practically and theoretically. It is much much tougher than the other things that you are dealing with. So that is one of the reasons why they do not talk about it, because it is very hard to understand what is going on. But it has practical applications as well. So, from that comes out all kinds of things: diffusion rates in solutions, and so on, can be measured.
NMR goes off and does all kinds of things. Then, finally, it gets started with biology.
An initial protein looked terrible all the way across the spectrum. It looked like this. This is hydrogen. Later on, we started using Carbon-13. We did a lot of work on Nitrogen-15. We had the first practical Nitrogen-15 machine. We did a lot of work with that kind of thing, to develop methods and show where they could be used.
It turned out that way, but not right away.
The trouble is that there is only a little tiny bit of Nitrogen-15 in ordinary nitrogen. That is one problem.
The other problem is that it has one tenth the magnetic moment of a proton.
You combine these things — the natural abundance and the magnetic moment — and you find that you are way way down on the scale.
Now, in order to really do this in the broad way, you can use ordinary compounds, or if you want to really do something important and do it well, you can use Nitrogen-15 that has been enriched. That is extremely expensive because it is hard to do. Then you have to turn that into a compound you are interested in.
There are commercial businesses that do that now for biologists and chemists. We use it whenever we can, because it makes gathering the signal very much easier.
Now, what we were doing originally was to use what one of my friends told me to do.
He said, [I cannot understand the tape]. [laughs]
Rather than trying to do it in a five millimeter tube, say, like this. We had a tube that was about that big.
Now, of course, it takes a lot more material than this does.
When a biologist would come, and I would say to him, “Well, you have to have enough to put in here at high concentration in order to get the spectrum, they would walk away. [again I cannot understand the tape]
There are plenty of compounds available, including biological compounds that you can get easily in this form.
Proteins are available in large quantities and a lot of natural products. We ran everything including marijuana.
But this is where you find out what works well. We did vitamin B-12, for example, which is a very big molecule.
We could see the individual lines of certain kinds of compounds.
Pavlish:What was the most interesting thing to you at this point? Was it finding out more about the compounds? Take vitamin B-12 for example. Was it understanding vitamin B-12 better for itself, and having different techniques going at the same time? Or, was it that NMR was so cool that you just wanted to put as many things in the NMR machine and find out more about as many things as possible through that technique?
Roberts:We did both. We did both. We worked on proteins for example. An important enzyme reaction was the hydrolysis of proteins. So-called protease.
I had a very very good guy.
We had to make the enzymes with Nitrogen-15 located in just the right spot in the big big molecule with a molecular weight of about 15,000. So we had to get one nitrogen into it at a particular time and another compound had to have two nitrogens in it. We ran those things and we got beautiful results out of them.
People did not like them very much because they did not fit with the hypothesis that was going on at that time. [laughs]
But that has been forgotten now and people are using the idea.
We did a lot of things that were just collecting data to see what we could do.
For example, we managed to get spectra of TRNA and then we found some interesting things, that if we changed the temperature, relaxation effects got mixed into it. That was very interesting. Peaks would appear and disappear.
Those ideas have been worked on by other people.
Pavlish:So you had a laboratory in this building?
Roberts:Oh yes. Yes.
We had a couple of labs here.
I usually would operate with graduate students somewhere between six and ten people.
If you look over at this pile here, you will see a young man there in front of a globe. [laughs] He was one of my graduate students. I just got something the other day in which he is rated as the number one living man in the field today, with the highest impact in chemistry.
Pavlish:Really? What is his name?
Roberts:He is a Harvard professor. George Whitesides.
I am proud of him. [laughs] He is a great guy.
Pavlish:Does he still do NMR? Did he work with you on NMR?
Roberts:He worked on everything. He worked in biology, he worked in physics, he worked in chemistry, and he worked in engineering.
He does very imaginative things.
His strong point is that he starts things and lets other people more or less carry them on after.
He has 45 people working for him.
Not my style. [laughs]
He is an advisor to the government.
He is all over the place.
If you could somehow get connected up to him, if you are doing history, you would be doing pretty well.